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Special populations

25 evidence topics · 7 sources

Pregnancy: risk summary

“There are no available data on HOVILPRI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.” (opens the prescribing information at this quote)
“The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.” (opens the prescribing information at this quote)
“In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.” (opens the prescribing information at this quote)

Pregnancy risk summary: no adverse developmental effects in animal reproduction studies

“In animal reproduction studies, no” (opens the prescribing information at this quote)
“adverse developmental effects were observed when pritelivir was administered to rats and rabbits at exposures (AUC) approximately 16- (rats) and 2- (rabbits) times the systemic pritelivir exposure in humans at the therapeutic dose of 100 mg” (opens the prescribing information at this quote)

Pregnancy: embryo-fetal development studies in rats and rabbits

“Pritelivir was administered orally to pregnant rats at 30, 200 and 1,000 mg/kg/day from gestation days 6 to 17 and to pregnant rabbits at 5, 20, 40, 60 and 80 mg/kg/day from gestation days 6 to 20.” (opens the prescribing information at this quote)
“In both species, developmental toxicities were only observed at maternally toxic doses, ≥200 mg/kg/day in the rat, and ≥40 mg/kg/day in the rabbit, resulting in low birth weights in both species, skeletal variations in the rat and fetal loss in rabbits at doses ≥60 mg/kg/day.” (opens the prescribing information at this quote)
“No adverse maternal or embryofetal effects were observed in rats at the low dose (30 mg/kg/day) and rabbits at 20 mg/kg/day resulting in systemic pritelivir exposures (AUC) approximately 5-times for rat, and equal to the human exposure at the therapeutic dose of 100 mg, for rabbits.” (opens the prescribing information at this quote)

Pregnancy: prenatal and postnatal development study in rats

“In the prenatal and postnatal development study, pritelivir was orally administered to pregnant rats at 25, 75 and 150 mg/kg/day from gestation day 6 to postpartum/lactation day 20.” (opens the prescribing information at this quote)
“Maternal toxicity occurred at 75 and 150 mg/kg/day resulting in fetal loss, lower birth weights and a delay in sexual maturation but with no influence on physical, functional, or reproductive development.” (opens the prescribing information at this quote)
“No adverse effects were observed in the offspring at 25 mg/kg/day resulting in maternal systemic pritelivir exposures (AUC) approximately 5-times the human exposure at the therapeutic dose of 100 mg.” (opens the prescribing information at this quote)

Pregnancy: published preliminary embryo-fetal development study in mice

“Pritelivir was administered by oral gavage to time-mated mice at dose levels of 0, 10, 60 and 200 mg/kg/day from gestational day 6 through 15.” (opens the source at this quote in a new tab)
“The results showed that exposure to pritelivir did not cause maternal or developmental toxicity in mice.” (opens the source at this quote in a new tab)
“Thus, both maternal and fetal no-observed-adverse-effect-level of pritelivir was determined to be 200 mg/kg/day.” (opens the source at this quote in a new tab)
“At this dose, the area under the concentration-time curve for pritelivir at steady state in maternal animals was 20 times greater than reported in humans at the clinical dose of 100 mg/day.” (opens the source at this quote in a new tab)
“Placenta-to-maternal plasma and fetus-to-maternal plasma concentration ratios in mice were 0.4 and 0.2, respectively, indicating transfer but not accumulation of pritelivir in the fetoplacental compartment.” (opens the source at this quote in a new tab)

Pregnancy: transfer across the perfused term human placenta ex vivo

“Our data demonstrated the transfer of pritelivir across the placenta ex vivo from the maternal to the fetal circuit and vice versa.” (opens the source at this quote in a new tab)
“Clearance index of pritelivir (ie, the transfer of pritelivir normalized to the transfer of a freely diffusible reference compound antipyrine) in the fetal-to-maternal direction (0.98 ± 0.07, n = 9) exceeded its clearance index in the maternal-to-fetal direction (0.86 ± 0.08, n = 9, P = .006), suggesting involvement of mechanisms other than diffusion in the placental disposition of this drug (possibly, efflux membrane transporters P-glycoprotein and breast cancer resistance protein that accept pritelivir as a substrate in vitro).” (opens the source at this quote in a new tab)
“Although our data suggested plausible fetal exposure to the drug, pritelivir did not affect the production of lactate, the consumption of glucose and oxygen, and the release of human chorionic gonadotropin from the perfused placental tissue, indicating its favorable safety profile.” (opens the source at this quote in a new tab)
“Moreover, pritelivir did not alter the viability of the tested cells in vitro.” (opens the source at this quote in a new tab)
“Further preclinical developmental toxicity studies of PRV are required in support of development of PRV for pregnant patients.” (opens the source at this quote in a new tab)

Lactation

“There are no data on the presence of pritelivir or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.” (opens the prescribing information at this quote)
“The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HOVILPRI and any potential adverse effects on the breastfed infant from HOVILPRI or from the underlying maternal condition.” (opens the prescribing information at this quote)

Pregnancy and breastfeeding as stated in the patient information

“are pregnant or plan to become pregnant. It is not known if HOVILPRI will harm your unborn baby.” (opens the prescribing information at this quote)
“are breastfeeding or plan to breastfeed. It is not known if HOVILPRI passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you take HOVILPRI.” (opens the prescribing information at this quote)

Females and males of reproductive potential: infertility

“There are no data on the effect of pritelivir on human fertility.” (opens the prescribing information at this quote)
“A fertility study of pritelivir in rats (50, 150 and 500 mg/kg/day) showed adverse effects on male fertility at 500 mg/kg/day.” (opens the prescribing information at this quote)
“Male rats dosed at 500 mg/kg/day exhibited direct effects on epididymal sperm counts, sperm motility and morphology and a minor increase in severity in lumen detritus in the epididymis.” (opens the prescribing information at this quote)
“At 150 mg/kg/day, male rats exhibited slight reduction of epididymal sperm counts as well as minor changes in sperm morphology.” (opens the prescribing information at this quote)
“The effects were confirmed to be reversible after 6 weeks of discontinuing pritelivir with no lasting adverse effects on male reproduction.” (opens the prescribing information at this quote)
“Male- mediated effects on early embryonic development occurred at 150 and 500 mg/kg/day (i.e., increase in fetal loss in treated and untreated females).” (opens the prescribing information at this quote)
“No effects on fertility or the offspring occurred at 50 mg/kg/day approximately 6-times the human exposure (AUC) at the therapeutic dose of 100 mg.” (opens the prescribing information at this quote)
“Sexually mature male monkeys dosed at 1,000 mg/kg/day for 39 weeks had no findings in the reproductive organs or semen” (opens the prescribing information at this quote)

Nonclinical toxicology: impairment of fertility

“In fertility studies in rats, doses of pritelivir at 50, 150, or 500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 7 of pregnancy.” (opens the prescribing information at this quote)
“Treatment related effects on male fertility including an increase in fetal loss, reduced sperm counts, and morphological and functional deficits in sperm were evident in rats at 500 mg/kg/day because of progressive disturbances to the primary and secondary sex organs.” (opens the prescribing information at this quote)
“These effects were no longer apparent after a 6-week recovery, indicating full reversibility.” (opens the prescribing information at this quote)
“There were no effects on fertility, mating or early embryonic development in females dosed with 150 mg/kg/day and males at 50 mg/kg/day resulting in systemic pritelivir exposures (AUC) approximately 6-times the human exposure at the therapeutic dose of 100 mg.” (opens the prescribing information at this quote)
“Of note, no effects on the reproductive organs or semen were seen in male sexually mature monkeys over a 39-week treatment period with 1,000 mg/kg/day.” (opens the prescribing information at this quote)

Pediatric use

“The safety and efficacy of HOVILPRI have not been established in pediatric patients 18 years of age and younger.” (opens the prescribing information at this quote)
“It is not known if HOVILPRI is safe and effective in children less than 18 years of age.” (opens the prescribing information at this quote)

Minimum age in the PRIOH-1 registry record

“Immunocompromised men and women of any ethnic group aged ≥16 years.” (opens the source at this quote in a new tab)
“In Canada, Germany, Belgium: Immunocompromised (due to conditions including but not limited to HIV infection, hematopoietic cell or solid organ transplantation, and chronic use of immunosuppressive treatment) men and women of any ethnic group aged >18 years.” (opens the source at this quote in a new tab)

Pediatric development plan agreed with the European Medicines Agency

“Treatment of acyclovir-resistant mucocutaneous herpes simplex infections in immunocompromised paediatric patients from 6 years to less than 18 years of age.” (opens the source at this quote in a new tab)
“the paediatric population from birth to less than 6 years of age;” (opens the source at this quote in a new tab)
“on the grounds that clinical studies with the specific medicinal product cannot be expected to be of significant therapeutic benefit to or fulfil a therapeutic need of the specified paediatric subset(s).” (opens the source at this quote in a new tab)
“Development of an oral suspension prepared from the film-coated tablets.” (opens the source at this quote in a new tab)
“Open-label, multi-centre trial to assess the pharmacokinetics, safety and clinical activity of pritelivir (mesylate monohydrate) in immunocompromised paediatric patients from 6 years to less than 18 years of age with mucocutaneous herpes simplex infection” (opens the source at this quote in a new tab)
“Date of completion of the paediatric investigation plan: By February 2029” (opens the source at this quote in a new tab)

Pediatric use outside the label: case series in allogeneic transplant recipients

“A total of eight patients were identified with acyclovir‐resistant HSV at Royal Manchester Children's Hospital between 2012 and 2025.” (opens the source at this quote in a new tab)
“Patients were aged between 1.5 and 17 years old and included 62.5% males” (opens the source at this quote in a new tab)
“Pritelivir was provided on compassionate access for two cases in our series” (opens the source at this quote in a new tab)
“but there was significant delay (> 20 days) between application, approval, and arrival of the drug and its duration of use was limited by the supplier.” (opens the source at this quote in a new tab)
“In addition, for the three patients who were treated with third‐line antivirals, only one had a good clinical response with resolution of their infection.” (opens the source at this quote in a new tab)
“This is even more challenging for pediatric patients, for whom there is no safety data or licensing.” (opens the source at this quote in a new tab)

Geriatric use

“Of the 51 immunocompromised participants treated with HOVILPRI in the Phase 3 PRIOH-1 Part C trial, 20% (10/51) were 65 years and older and 4% (2/51) were 75 years of age and older (range 19-84 years)” (opens the prescribing information at this quote)
“No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.” (opens the prescribing information at this quote)

Renal impairment: dosing recommendation

“No dose adjustment is recommended for patients with mild, moderate, or severe renal impairment.” (opens the prescribing information at this quote)
“The pharmacokinetics and safety of pritelivir in patients requiring hemodialysis have not been evaluated” (opens the prescribing information at this quote)

Renal impairment: pharmacokinetics in the prescribing information

“In a single-dose pharmacokinetic study, pritelivir exposure (AUC and Cmax) was comparable between participants with mild (eGFR 60–89 mL/min) or moderate (eGFR 30–59 mL/min) renal impairment and those with normal renal function (eGFR ≥90 mL/min).” (opens the prescribing information at this quote)
“Pritelivir exposure (AUC and Cmax) were approximately 1.6- fold higher in participants with severe renal impairment (eGFR 15–29 mL/min, not on hemodialysis) relative to those with normal renal function.” (opens the prescribing information at this quote)
“Pritelivir pharmacokinetics in patients on hemodialysis is unknown.” (opens the prescribing information at this quote)

Hepatic impairment: dosing recommendation

“No dose adjustment is recommended for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.” (opens the prescribing information at this quote)
“The pharmacokinetics and safety of pritelivir in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated” (opens the prescribing information at this quote)

Hepatic impairment: pharmacokinetics in the prescribing information

“In a single-dose pharmacokinetic study, pritelivir exposure (AUC and Cmax) was comparable in participants with moderate hepatic impairment (Child-Pugh Class B) relative to those with normal hepatic function.” (opens the prescribing information at this quote)
“The effect of severe hepatic impairment (Child-Pugh Class C) on pritelivir pharmacokinetics is unknown.” (opens the prescribing information at this quote)

Renal and hepatic impairment trials: design and participants

“The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects.” (opens the source at this quote in a new tab)
“In total, 32 healthy subjects (20 men, 12 women) were enrolled in the trial, with 8 subjects included in each of the following groups: control, mild, moderate, and severe renal impairment.” (opens the source at this quote in a new tab)
“In total, 16 healthy subjects (8 men, 8 women) were enrolled in the trial, with 8 subjects included in each of the following groups: control and moderate hepatic impairment.” (opens the source at this quote in a new tab)
“In both trials, the effect of impairment was evaluated after administration of a single oral dose of 100 mg of pritelivir.” (opens the source at this quote in a new tab)
“All subjects in the hepatic impairment group had Child-Pugh total scores within the prespecified range (7-9), and the full range of scores representing moderate hepatic impairment was included.” (opens the source at this quote in a new tab)

Renal and hepatic impairment trials: pritelivir exposure ratios against matched controls

Comparison with matched controls	Parameter	Least squares means ratio (%)	90% confidence interval (%)
Mild renal impairment	Total Cmax	“89.5”	“52.0-153.9”
Mild renal impairment	Total AUC0-inf	“88.8”	“61.2-128.7”
Mild renal impairment	Unbound AUC0-inf	“86.9”	“58.1-130.0”
Moderate renal impairment	Total Cmax	“100.0”	“58.1-171.9”
Moderate renal impairment	Total AUC0-inf	“106.9”	“73.7-155.0”
Moderate renal impairment	Unbound AUC0-inf	“108.0”	“72.2-161.6”
Severe renal impairment	Total Cmax	“160.7”	“93.4-276.4”
Severe renal impairment	Total AUC0-inf	“156.7”	“108.0-227.1”
Severe renal impairment	Unbound AUC0-inf	“161.8”	“108.1-242.1”
Moderate hepatic impairment	Total Cmax	“113.0”	“66.4-192.1”
Moderate hepatic impairment	Total AUC0-inf	“95.5”	“69.7-130.8”
Moderate hepatic impairment	Unbound Cmax	“145.7”	“86.4-245.8”
Moderate hepatic impairment	Unbound AUC0-inf	“123.2”	“85.1-178.4”

Renal impairment trial: pritelivir exposure, clearance, and half-life

“Following a single oral dose of 100 mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir.” (opens the source at this quote in a new tab)
“In subjects with severe renal impairment, systemic exposure (based on AUC0-inf) was 57% higher compared with matched control subjects.” (opens the source at this quote in a new tab)
“This could not be attributed to a lower renal excretion or altered plasma protein binding but was more likely due to changes in drug metabolism and transport pathways in the liver and intestine, which is more pronounced in subjects with severe renal impairment.” (opens the source at this quote in a new tab)
“CL/F of pritelivir was similar (range, 1.4-1.6 L/h) among control, mild, and moderate renal impairment categories and lower for subjects with severe renal impairment (0.8 L/h).” (opens the source at this quote in a new tab)
“Mean t1/2z for pritelivir and metabolites were comparable among the matched control subjects and all renal impairment categories (range, 54.9-56.3 hours).” (opens the source at this quote in a new tab)
“The free fraction was similar among renally impaired and matched control subjects.” (opens the source at this quote in a new tab)

Renal impairment trial: metabolite exposure

“For the metabolite PPA, the LS means ratios for AUCinf were 94.6%, 132.8%, and 296.9% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab)
“For the metabolite ATS, the LS means ratios for AUCinf were 96.1%, 167.3%, and 259.7% and for the metabolite PPA-acyl glucuronide, the LS means ratios for AUC0-inf were 104.2%, 201.7%, and 559.4% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab)
“These results were not unexpected, as the primary route of excretion for metabolites is renal and about 77% of pritelivir-related material was recovered in urine.” (opens the source at this quote in a new tab)

Hepatic impairment trial: unbound exposure, clearance, half-life, and metabolites

“Free fraction was higher for subjects with moderate hepatic impairment compared with matched control subjects, resulting in a 23% higher systemic exposure of unbound pritelivir.” (opens the source at this quote in a new tab)
“Mean fu was slightly higher for subjects with moderate hepatic impairment (0.738%) compared with matched control subjects (0.551%).” (opens the source at this quote in a new tab)
“For pritelivir, mean t1/2z and CL/F were comparable for subjects with moderate hepatic impairment (45.9 hours and 1.3 L/h, respectively) and matched control subjects (52.0 hours and 1.3 L/h, respectively) with overlapping ranges.” (opens the source at this quote in a new tab)
“For the metabolites PPA, ATS, and PPA-acyl glucuronide, the LS means ratios for AUC0-inf were 122.2%, 168.8%, and 95.1%, respectively, for subjects with moderate hepatic impairment compared with matched control subjects.” (opens the source at this quote in a new tab)
“While the renal impairment trial included subjects with mild, moderate, and severe renal impairment, the hepatic impairment trial included subjects with moderate hepatic impairment only, which is generally considered appropriate,” (opens the source at this quote in a new tab)
“observations from the moderate hepatic impairment group could be applied to subjects with mild hepatic impairment as well.” (opens the source at this quote in a new tab)

Renal and hepatic impairment trials: adverse events

“In the renal impairment groups treated with pritelivir, 6 subjects had a total of 6 TEAEs (1 per subject), of which 1 of 8 subjects (12.5%) each was in the mild and moderate impairment groups and 4 of 8 subjects (50.0%) were in the severe renal impairment group.” (opens the source at this quote in a new tab)
“Only 1 subject (12.5%) in the mild renal impairment group had 1 TEAE (headache) considered to be possibly related to pritelivir.” (opens the source at this quote in a new tab)
“In the hepatic impairment group treated with pritelivir, 4 of 8 subjects (50%) had a total of 4 TEAEs (1 per subject).” (opens the source at this quote in a new tab)
“The events were generally consistent with the selected hepatically impaired population and none of the TEAEs were considered to be related to pritelivir.” (opens the source at this quote in a new tab)